Limited data are available on the off-label use of drug-eluting stents (DESs) in clinical practice. We used data from the American College of Cardiology National Cardiovascular Data Registry to describe the rates and outcomes of DES use in 4 common off-label situations: ST-elevation myocardial infarction, in-stent restenosis, coronary artery bypass grafts, and chronic total occlusions. The rates of in-hospital adverse events for each off-label situation were determined and compared with the expected rates calculated from a validated model. From approval of DESs to the end of 2004, a total of 408,033 procedures involved placement of a DES. The use of DESs increased from 19.7% at the start of the study to 78.2% by the end of fourth quarter of 2004. Off-label use of DESs occurred in 24.1% of procedures. The rates of in-hospital adverse events with DES use in ST-elevation myocardial infarction, in-stent restenosis, coronary artery bypass grafting, and chronic total occlusions were lower than expected from the validated model. In conclusion, off-label use of DESs is common and is associated with a low rate of short-term adverse events. Randomized clinical trials are needed to confirm the efficacy of DESs in these clinical and angiographic settings. These data also highlight the importance of multicenter registries in tracking new technologies.